Back to EveryPatent.com
United States Patent | 5,756,548 |
Flitter ,   et al. | May 26, 1998 |
A group of benzamide compounds are disclosed which are useful for treating neurodegenerative disorders. Methods for making these compounds are provided. These materials are formed into pharmaceutical compositions for oral or intravenous administration to patients suffering from conditions such as Parkinson's disease which can exhibit themselves as progressive loss of central nervous system function. The compounds can arrest or slow the progressive loss of function.
Inventors: | Flitter; William (Mountain View, CA); Garland; William (Cupertino, CA); Paylor; Richard (Sunnyvale, CA); Wilcox; Allan (Fremont, CA) |
Assignee: | Centaur Pharmaceuticals, Inc. (Sunnyvale, CA) |
Appl. No.: | 812138 |
Filed: | March 6, 1997 |
Current U.S. Class: | 514/616; 564/153; 564/155; 564/156 |
Intern'l Class: | A61K 031/165; C07C 233/05; C07C 233/65 |
Field of Search: | 564/153,155,156 514/616,619 |
4927928 | May., 1990 | Shroot et al. | 544/154. |
5212203 | May., 1993 | Shroot et al. | 514/617. |
5346691 | Sep., 1994 | Raspanti et al. | 424/59. |
5472983 | Dec., 1995 | Flitter et al. | 514/599. |
Foreign Patent Documents | |||
0 401 903 | Dec., 1990 | EP. | |
58-67656 | Apr., 1983 | JP. | |
1047028 | Nov., 1966 | GB. | |
1 505 633 | Mar., 1978 | GB. | |
2244704 | Dec., 1991 | GB. | |
2244704 | Aug., 1995 | GB. | |
WO 93/15047 | Aug., 1993 | WO. | |
WO 94/27584 | Dec., 1994 | WO. | |
WO 95/28153 | Oct., 1995 | WO. |
Freter et.al., Liebigs Ann. Chem., 811-820, 1973. R.W. Hartman et al., Eur. J. Med. Chem. (1994) 29, 807-817. L.A. Errede, et al., J. Org. Chem. (1977) 42(4) 656-658. EPO Patent Abstracts of Japan, vol. 7, No. 155, and Derwent Abstract No. 83-52581K (Abstracts of Japanese Publication No. JP 58067657, published Apr. 22, 1983). EPO Patent Abstracts of Japan, vol. 6, No. 90, and Derwent Abstract No. 82-20427E (Abstracts of Japanese Publication No. JP 57021320, published Feb. 4, 1982). Chemical Abstract No. 61:13221d (1964) (Abstract 15 of M. Melandri, et al., Bull. Chim. Farm. 103, 475-489). Chemical Abstract No. 58:4541a (1963) (Abstract of M. Itaya, et al., Yakugaku Zasshi (1962) 82, 634-639). Banasik et al., "Specific inhibitors of poly(ADP-Ribose) synthase and mono(ADP-ribosyl)transferase" J. Biol. Chem. (1992) 267:1569-1575. Beal, M.F. in Mitochondrial Dysfunction and Oxidative Damage in Neurodegenerative Diseases, R.G. Landes Publications Austin, TX, (1995) pp. 53-61 and 73-99. Bishop et al., "Synthesis and in vitro evaluation of 2,3-dimethoxy-5-(fluoroalkyl)-substituted benzamides: high-affinity ligands for CNS dopamine D.sub.2 receptors" J. Med. Chem. (1991) 34:1612-1624. Burns, R.S., et al., "A Primate Model of Parkinsonism . . . " Proc. Natl. Acad. Sci. USA (1983) 80:4546-4550. Calne, D.B., "Treatment of Parkinson's Disease" NEJM (Sep. 30, 1993) 329:1021-1027. El Tayar, et al., "Interaction of neuroleptic drugs with rat striatal D-1 and D-2 dopamine receptors: a quantitative structure--affinity relationship study" Eur. J. Med. Chem. (1988) 23:173-182. Gerlach, M. et al., "MPTP Mechanisms of Neurotoxicity and the Implications for Parkinson's Disease" European Journal of Pharmacology (1991) 208:273-286. Heikkila, R.E., et al., "Dopaminergic Neurotoxicity of 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine in Mice" Science (Jun. 29, 1984) 224:1451-1453. Hogberg et al., "Potential antipsychotic agents. 9. Synthesis and stereoselective dopamine D-2 receptor blockade of a potent class of substituted (R)-N-›benzyl-2-pyrrolidinyl)methyl!benzamides. Relations to other side chain congeners" J. Med. Chem. (1991) 34:948-955. Kato, T., "Reaction of Triethyloxonium Fluoroborate with Acid Amide. III.sup.1) Formation of Quinazoline and 4H-3, 1-Benzoxazin-4-one Derivatives", Chem. Pharm. Bull. (1976) 24, 3:431-436. Katopodis et al., "Novel substrates and inhibitors of peptidylglycine .alpha.-amidating monooxygenase" Biochemistry (1990) 29:4541-4548. Langston, J.W., et al., "Chronic Parkinsonism in Humans Due to a Product of Meperidine-Analog Synthesis" Science (Feb. 25, 1983) 219, 979-980. Marsden, C.D., in "Review Article--Parkinson's Disease" Lancet (Apr. 21, 1990) 948-952. Mizuno, Y., Mori, H., Kondo, T. "Potential of Neuroprotective Therapy in Parkinson's Disease" CNS Drugs (1994) 1:45-46. Monkovic et al., "Potential non-dopaminergic gastrointestinal prokinetic agents in the series of substituted benzamides" Eur. J. Med. Chem. (1989) 24:233-240. Rainnie et al., "Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal" Science (1994) 263:689-690. Singer, T.P., et al., "Biochemical Events in the Development of Parkinsonism . . . " J. Neurochem. (1987) 1-8. |
TABLE 1 ______________________________________ Efficacy of CPI Compounds 1189, 1160, and 1234 at 30 mg/kg in the 15 mg/kg MPTP Model. NANOMOLES DOPAMINE PER % NON-MPTP COMPOUND MG PROTEIN .+-. S.E.M. CONTROL ______________________________________ methyl cellulose 0.72 .+-. .05 54.1 CPI1160 1.25 .+-. .05 93.9 CPI1234 1.02 .+-. .05 76.7 methyl cellulose 0.56 .+-. .07 36.4 CPI1189 1.37 .+-. .14 89.7 ______________________________________
TABLE 2 ______________________________________ Comparison of the Efficacies of CPI1189 and CPI1020 at 50 mg/kg in the 15 mg/kg MPTP Model. NANOMOLES DOPAMINE PER COMPOUND MG PROTEIN .+-. S.E.M. ______________________________________ CPI1020 0.58 .+-. .14 CPI1189 1.57 .+-. .11 ______________________________________